There are no issues that I know of that cause problems with backup jobs that span more than one tape other than needing to have a tape changer, unless you plan on manually changing tapes in the middle of the job.
Personally I try to keep my jobs from spanning tapes simply to alleviate the tape management headache. I do have a job that spans tapes, and I have not experienced any problems with the media pools. The sequence one tape for a job is all that is listed in the save set, but both the sequence one and the sequence two are listed in the scratch set. The job then overwrites both tapes in order.
If you use ARCServeIT's GFS rotation, three media polls are created for each job.